Uric acid is the end product of purine bodies in human. The upper limit of normal uric acid concentration solved in plasma is 7.0 mg/dL independently from sex and age, and the condition with higher concentration is clinically defined as hyperuricemia. Hyperuricemia affects mostly in adult men and is considered to result from combination of a genetic factors involved in metabolism of purine bodies and secondary factors such as consumption of a high-energy food, nucleic acid rich food or the like. Conditions of persistent hyperuricemic increase a risk of developing arthritis following to urate crystal deposition in intra- or peri-joints. The condition with such developed arthritis is called gout, and the arthritis is called gouty attack. Hyperuricemia is classified broadly into types consisting of a uric acid overproduction-type wherein the uric acid production increases, a uric acid underexcretion-type wherein the uric acid excretion in urine decreases, and a mixed type of them (for example, see Non-patent References 1 and 2).
In the prevention or treatment of hyperuricemia or gout, the basis is to control the plasma uric acid level under a certain level to prevent the incidence of gouty arthritis, and the incidence of the gouty arthritis is considered the lowest in the case to control plasma uric acid level within the range from 4.6 to 6.6 mg/dL. So far, for the treatment of hyperuricemia or gout, allopurinol of a uric acid synthesis inhibitor or probenecid, bucolome, benzbromarone of uricosuric drugs or the like have been used for the improvement of the plasma uric acid level. In addition, in the treatment of gouty attacks, an agent for the pain attack such as colchicine, a nonsteroidal anti-inflammatory agent such as indometacin, naproxen, fenbufen, pranoprofen, oxaprozin, and an adrenocortical steroid are used (for example, see Non-patent Reference 1).
Allopurinol of a uric acid synthesis inhibitor has side effects such as poisoning syndrome (hypersensitivity angiitis), Stevens-Johnson syndrome, exfoliative dermatitis, a plastic anemia, hepatic insufficiency or the like. In addition, a uricosuric drug has a restriction not to be used for a patient with renal failure, and probenecid, bucolome and benzbromarone have side effects such as gastrointestinal disorder, urinary lithiasis, and especially, benzbromarone sometimes causes fulminant hepatic failure in a patient with idiosyncrasy (for example, see Non-patent Reference 1).
It has been desired to develop a new preventative or therapeutic drug having few side effects which can solve such problems of these existing drugs, especially one with a different mechanism compared with existing drugs from the viewpoint of broadening the choices of treatment methods.
Since hyperuricemia is brought on by life style such as overeating, food preference for high purine, high fat or high protein, habitual drinking, insufficient exercise or the like and highly correlated with obesity, hypertension, abnormality in the metabolism of sugar or lipid or the like, life style guidance plays an important role as a non-drug therapy in order to correct the life style. In particular, dietary therapy to avoid excessive intake of purine has a major rule. However, it is difficult to continue such diet therapy and improvement of the life style, and they often fail.
On the digestion and absorption pathway of nucleic acid in human, nucleic acids which are released in the intestine from a nucleic acid or nucleoproteins ingested are broken down into mononucleotides by ribonucleases, deoxyribonucleases and polynucleotidases, furthermore, it is considered that the pathway wherein mononucleotide is degraded into nucleoside by nucleotidases and phosphatase and then the nucleosides are absorbed is the main pathway. In the pathway, it is considered that the absorbed purine nucleoside is changed to uric acid (for example, see Non-patent Reference 3). As other pathways, it can be suspected that nucleoside is broken down to form purine base and then absorbed, or purine base contained in food is directly absorbed. However, these pathways have not been yet unexplained in detail.
Membrane proteins called nucleoside-transporter relate to the nucleoside uptake in the intestine. As such transporters, there are Equilibrative transporters which have transport process of nucleoside into the cell by the concentration gradient of nucleoside (hereinafter referred to as ENT) and sodium-dependent nucleoside transporters which are driven by the concentration gradient of ion between in and out of the cell (hereinafter referred to as CNT) in mammalian cells (for example, see Non-patent Reference 4). As human nucleoside transporters, two types of ENT, Type 1 (hereinafter referred to as ENT1) and Type 2 (hereinafter referred to as ENT2), have been identified and cloned so far (for example, see Non-patent References 5 and 6). In addition, three types of CNT, Type 1 (hereinafter referred to as CNT1), Type 2 (hereinafter referred to as CNT2) and Type 3 (hereinafter referred to as CNT3) have been identified and cloned (for example, see Non-patent References 7 to 9).
The distribution and characteristics of these transporters have been confirmed to some extent. Regarding ENTs, both ENT1 and ENT2 are expressed broadly in human normal tissues and transport both purine and pyrimidine nucleosides. In terms of function, their sensitivities to nitrobenzylthioinosine (hereinafter referred to as NBMPR) are different, that is, ENT1 is markedly inhibited by a low concentration of NBMPR (IC50<5 nM), while ENT2 is hardly inhibited by NBMPR, but is inhibited only by a high concentration of NBMPR (IC50>1 μM) (for example, see Non-patent Reference 10).
On the other hand, regarding CNTs, CNT1 transports pyrimidine nucleoside and adenosine, and the messenger RNA (hereinafter referred to as mRNA) has been confirmed to be expressed in the jejunum and kidney in rats. CNT2 transports purine nucleoside and uridine, and various kinds of mRNA have been confirmed to be expressed in organs including the heart, liver, skeletal muscles, kidney, intestines or the like in human. CNT3 has been recently cloned and transports, both purine and pyrimidine nucleosides, and the mRNA has been confirmed to be expressed in the bone marrow, pancreas, intestines and mammary gland in human. In addition, in terms of function, it has been confirmed that all of these CNTs are not influenced by NBMPR (for example, see Non-patent References 9 and 11).
In addition, in the previous studies on transport mechanism in the intestines, it is shown that purine bodies are absorbed through CNT from mucosal side in small intestinal epithelial cells and transported to blood side through ENT exiting in serosal side (for example, see Non-patent Reference 12). However, the contribution of nucleoside transporters to purine absorption in the human intestines, especially in the human small intestine has been not clarified in detail.
On the other hand, in Patent References 1 and 2, it has been reported that plasma uric acid level is lowered by inhibiting purine absorption. Additionally, it was confirmed that plasma uric acid level is lowered by restriction on eating dietary sources of purine in human. Therefore, uric acid synthesized from purine nucleosides absorbed in the intestine reflects plasma uric acid concentration (for example, see Non-patent Reference 13), plasma uric acid level can be controlled by effective inhibition of the purine nucleoside absorption through the intestines.
By the way, it was reported that regarding an 8-modified purinenucleoside derivative, that is useful for the treatment of hepatitis C virus (see Patent Reference 3), and 8-bromoadenosine exhibits a weak inhibitory activity against CNT (for example, see Non-patent Reference 14). However, any 8-modified purinenucleoside derivative has not been reported. Furthermore, it has not ever been reported or suggested that an 8-modified purinenucleoside derivative of the present invention has an inhibitory activity against CNT and is useful for the prevention or treatment of a disease associated with an abnormality of plasma uric acid level such as gout, hyperuricemia or the like.    Patent Reference 1: Japanese Patent Publication 2001-163788;    Patent Reference 2: Japanese patent no. 2632577; Patent Reference 3: International Publication WO2002/18404;    Non-patent Reference 1: Edited by the committee drafting Guideline for the management of hyperuricemia and gout, Guideline for the management of hyperuricemia and gout, Digest version, published by Jananse Society of Gout and Nucleic Acid Metabolism, Sep. 1, 2002 pp. 1-9;    Non-patent Reference 2: Astuo Taniguchi and 1 person, Shindan to Chiryo (Diagnosis and Treatment), 2002, Vol. 90, No. 2, pp. 186-191;    Non-patent Reference 3: Harper's Biochemistry, the original edition 25, translated by Yoshito Kajiro, published by MARUZEN CO., LTD. Jan. 30, 2001, p. 417;    Non-patent Reference 4: Carol E. Cass and 11 persons, Membrane Transporters as Drug Targets, 1999, PP 318-321;    Non-patent Reference 5: Mark Griffiths and 10 persons, NATURE MEDICNE, January 1997, Vol. 3, No. 1, PP. 89-93;    Non-patent Reference 6: Charles R. Crawford and 3 persons, The Journal of Biological Chemistry, 1998, Vol. 273, No. 9, PP. 5288-5293;    Non-patent Reference 7: Mabel W. L. Ritzel and 5 persons, American Journal of Physiology, 1997, Vol. 272, Cell Physiology, Vol. 41, PP. C707-C714;    Non-patent Reference 8: Juan Wang and 5 persons, American Journal of Physiology, 1997, Vol. 273, Renal Physiology, Vol. 42, PP. F1058-F1065;    Non-patent Reference 9: Mabel W. L. Ritzel and 14 persons, The Journal of Biological Chemistry, 2001, Vol. 276, No. 4, pp. 2914-2927;    Non-patent Reference 10: Carol E. Cass and 11 persons, Membrane Transporters as Drug Targets, 1999, pp. 316-318;    Non-patent Reference 11: Carol E. Cass and 11 persons, Membrane Transporters as Drug Targets, 1999, pp. 327-332;    Non-patent Reference 12: James D. Young and 4 persons, Gastrointestinal transport, molecular physiology, 2001, pp. 334-337;    Non-patent Reference 13: N. Zollner, Proceedings of the Nutrition Society, 1982, Vol. 41, pp. 329-342;    Non-patent Reference 14: Patil S. D. and 2 persons, Cancer Chemotherapy Pharmacology, 2000, Vol. 46, No. 5, pp. 394-402.